Lewis acid-catalyzed stereospecific ring expansion of aziridine-2- carboxylates to imidazolidin-2-ones

Article abstract of DOI:10.1039/b503750f

Lewis acid-catalyzed ring expansion reaction of chiral aziridine-2- carboxylate proceeds regio- and stereospecifically to yield enantiomerically pure 4-functionalized imidazolidin-2-ones in high yields. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503750f

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COMMUNICATION
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Lewis acid-catalyzed stereospecific ring expansion of aziridine-2-
carboxylates to imidazolidin-2-ones{
Min Sung Kim,a Yong-Woo Kim,a Heung Sik Hahm,a Jae Won Jang,a Won Koo Lee*a and Hyun-Joon Ha*b
Received (in Cambridge, UK) 15th March 2005, Accepted 18th April 2005
First published as an Advance Article on the web 9th May 2005
DOI: 10.1039/b503750f
(2)-menthol ester 1 with 1.01 equiv. of phenyl isocyanate in
DMF at room temperature or under reflux but resulted in no
addition product. We realized that the isocyanate was not
electrophilic enough to form the aziridinium ion intermediate.
Therefore, we introduced Ti(OiPr)4 as a Lewis acid to activate the
isocyanate to become more electrophilic so that the aziridine ring
nitrogen can attack easily. This introduction of a Lewis acid still
did not provide the expected product leaving all the starting
material unreacted.
Lewis acid-catalyzed ring expansion reaction of chiral aziridine-
2-carboxylate proceeds regio- and stereospecifically to yield
enantiomerically pure 4-functionalized imidazolidin-2-ones in
high yields.
Cycloaddition of three-membered ring heterocycles with hetero-
cumulenes attracts a great deal of attention due to the potential
biological activity of the products.1 However, few successes with
activated aziridine have been reported with proper control of the
regio- and stereochemistry utilizing metals as catalysts.1k,l In this
report we would like to describe the first Lewis acid-catalyzed
regio- and stereospecific cycloaddition reaction involving aziridines
with isocyanates as a new simple stereospecific approach to
4-functionalized imidazolidin-2-one ring systems. Functionalized
imidazolidin-2-ones have been used not only as chiral synthons in
asymmetric syntheses of biologically active compounds or their
synthetic intermediates,2 but also as chiral auxiliaries in asym-
metric transformations.3 Moreover, some suitably substituted
chiral imidazolidin-2-ones are also being used as biologically
active compounds.4 In spite of their great variety of applicability,
only a few preparative methods exist for the target compounds
starting from b-keto esters,5 1,2-amino alcohols,6 oxime ethers,7
resin-bound amino acids,8 halocyclization,9 and aziridines.10
This Lewis acid-catalyzed cycloaddition reaction of aziridine-2-
carboxylates with isocyanates will serve as a facile and asymmetric
route to access functionalized imidazolidin-2-ones.
All those repeated failures reminded us of our previous one-step
transformation of aziridine-2-carboxylates into the corresponding
5-functionalized oxazolidin-2-ones.12a This previous work gave us
a new insight and led us to introduce Lewis acids containing halide
that could serve as both a nucleophile and a leaving group. The
reaction of the chiral aziridine 1 with 1.1 equiv of phenyl
isocyanate and 3.0 equiv. of TMSCl in DMF at an ambient
temperature proceeded smoothly to provide 89% yield of
imidazolidin-2-one-4(R)-carboxylic acid (2)-menthol ester 2a
(Scheme 1). After optimization of Lewis acids, solvents, concen-
trations, and temperature, we found that different reaction
conditions were needed for different isocyanates. Furthermore,
we realized that the introduction of a Lewis acid involving halide
makes the reactions proceed smoothly to afford the corresponding
imidazolidin-2-one 2a. We therefore proposed
a plausible
mechanistic pathway with retention of the configuration at C-2
of the aziridine via a double inversion process at the C-2 position
of the chiral aziridine. The C(2)–N bond is regiospecifically cleaved
by the bromide ion from MgBr2 or MgBr2?Et2O or by the chloride
ion from TMSCl via an SN2 process as in 3, and then the following
We reported the possibilities of the chiral aziridine as a three-
carbon chiral building block for the preparation of various amino
acid derivatives and biologically active natural products.11 We also
reported the preparation of enantiomerically pure functionalized
oxazolidin-2-ones starting from the commercially available chiral
aziridine using a single step ring expansion reaction.12 Throughout
our earlier studies we found that the nitrogen of the aziridine was
quite basic and also nucleophilic enough to participate in various
reactions. Therefore, we learned that the ring-opening reaction of
the aziridine was initiated by the formation of the aziridinium ion
intermediate. These results motivated us to explore a new efficient
method to obtain new ring expansion products, imidazolidin-2-
ones, from the reactions of the chiral aziridine-2-carboxylate with
various isocyanates.
An initial experiment was performed with the commer-
cially available N-[(R)-(+)-a-methylbenzyl]-2(R)-carboxylic acid
{ Electronic Supplementary Information (ESI) available: Synthetic
procedure and characterisation of all new compounds. See http://
www.rsc.org/suppdata/cc/b5/b503750f/
*wonkoo@sogang.ac.kr (Won Koo Lee)
hjha@hufs.ac.kr (Hyun-Joon Ha)
Scheme 1 Preparation of imidazolidin-2-ones with isocyanates and its
plausible mechanism.
3062 | Chem. Commun., 2005, 3062–3064
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Table 1 Preparation of imidazolidin-2-ones with isocyanatea
intramolecular cyclization by the urea amide nitrogen of 4 gives
the corresponding imidazolidinone 2 with retention of the
configuration at C-2 of the aziridine 1. Therefore, the presence
of a suitable Lewis acid is necessary and the same reaction without
the Lewis acid does not proceed at all.
Entry
R
Product
Yield (%)e
1
2
3
4
5
6
7
8
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
89
86
89
80
91
89
87
95
93
77
76
88
77
65
93
75
4-Biphenyl
1-Naphthyl
o-Tolyl
4-FPh
4-ClPh
3-MeOPh
4-MeOPh
2-NO2Ph
2,4-DiMeOPh
1,4-DiNCOPh
Bn
To confirm the absolute configuration at C-4 of the imidazo-
lidin-2-one 2, we carried out two additional experiments. N-[(R)-
(+)-a-methylbenzyl]-N9-benzylimidazolidin-2-one-4(R)-carboxylic
acid (2)-menthol ester 2l was obtained from the chiral aziridine 1
by the optimized reaction conditions using benzyl isocyanate. The
same compound imidazolidin-2-one 2l was obtained from
the compound 5, the intermediate of our previous work,12a by
the reaction with benzylamine with potassium carbonate in
CH3CN followed by intramolecular cyclization (Scheme 2). We
also obtained N-[(R)-(+)-a-methylbenzyl]-N9-tosyl-imidazolidin-2-
one-4-(R)-carboxylic acid (2)-menthol ester 2o from the chiral
aziridine 1 with tosyl isocyanate through the same reaction
conditions. Imidazolidin-2-one-4(R)-carboxylate 2o was reduced to
provide 4(R)-hydroxymethyl substituted imidazolidin-2-one 6o in
high optical purity with [a]D 5 +169 (c 5 0.16 in CHCl3) [lit.10b
[a]D 5 2165 (c 5 0.7 in CHCl3) for its enantiomer] whose
configuration was confirmed as stated.
9
10
11
12b
13b
14c
15d
16d
a
Et
Cyclohexyl
Ts
C(O)CCl3
Reactions were conducted with aziridine, 10 mol% MgBr2, 0.2 M
in dioxane and 1.01 equiv. of RNCO at room temperature, 12–48 h.
Reactions were conducted with aziridine, 10 mol% MgBr2?Et2O,
b
0.2 M in THF and 1.01 equiv. of RNCO at room temperature, 1 h.
Reactions were conducted with aziridine, 2.0 equiv. TMSCl, 0.2 M
c
in THF and 2.0 equiv. of RNCO at room temperature, 10 min.
Reactions were conducted with aziridine, 3.0 equiv. TMSCl, 0.2 M
d
in THF and 2.0 equiv. of RNCO at room temperature, 10 min.
Isolated yield.
e
The above mentioned stereospecific transformation of the
aziridine-2-carboxylic acid (2)-menthol ester 1 with phenyl
isocyanate proceeded well to give the corresponding enantiomeri-
cally pure imidazolidin-2-one-4(R)-carboxylic acid (2)-menthol
ester 2a as a white solid in 89% yield. We also confirmed the
retention of the configuration at C-2 of the aziridine by
using 2(S)-stereoisomer 1d to obtain the corresponding
4(S)-imidazolidin-2-one 2ad as an oil in 83% yield under the same
reaction conditions. This shows that the absolute configuration at
C-4 of the imidazolidin-2-one is controlled by that of the C-2
position of the chiral aziridines. As a result, enantiomerically pure
imidazolidin-2-one-4-carboxylates are available efficiently from the
corresponding aziridine-2-carboxylate using a ring expansion
reaction with various isocyanates with retention of the configura-
tion at the C-2 position of the aziridine-2-carboxylates (Table 1).
We used isocyanates with various substituents such as aryl (entries
1–11), alkyl (entries 12–14), tosyl (entry 15) and trichloromethyl-
carbonyl (entry 16) to provide a variety of structurally modified
enantiomerically pure imidazolidin-2-one-4-carboxylates in high
yields. We also functionalized imidazolidin-2-one-4-carboxylates 2
to the corresponding 4-hydroxylmethyl imidazolidin-2-ones 6, and
also to the corresponding amides 7 in high yields.
In conclusion, the enantiomerically pure N,N9-disubstituted
imidazolidin-2-one-4-carboxylates can be obtained in a one-step,
simple and highly efficient manner using a Lewis acid-catalyzed
ring expansion reaction of the commercially available chiral
aziridines with isocyanates. These reactions proceed both regio-
and stereospecifically with retention of the configuration at the C-2
of the chiral aziridines.{
The authors are grateful for financial support from the Korea
Science and Engineering Foundation (R01-2000-000-00048-0 and
the Center for Bioactive Molecular Hybrids to H.J.H.) and the
Korea Research Foundation (KRF-2002-070-C00060 to W.K.L.)
Min Sung Kim,a Yong-Woo Kim,a Heung Sik Hahm,a Jae Won Jang,a
Won Koo Lee*a and Hyun-Joon Ha*b
aProgram of Integrated Biotechnology, Department of Chemistry,
Sogang University, Seoul, 121-742, Korea.
E-mail: wonkoo@sogang.ac.kr; Fax: +82-2-701-0967;
Tel: +82-2-705-8449
bDepartment of Chemistry, Hankuk University of Foreign Studies,
Yongin, 449-791, Korea. E-mail: hjha@hufs.ac.kr;
Fax: +82-31-3304566; Tel: +82-31-3304369
Notes and references
{ General procedure for the synthesis of imidazolidin-2-one-4-carboxylates
via MgBr2-catalyzed reaction: preparation of N-[(R)-(+)- a-methylbenzyl]-
N9-(R)-imidazolidin-2-one-4-carboxylates (2a). To a solution of 1 (100 mg,
0.30 mmol) in 1.80 mL of dioxane was added PhNCO (37 mL, 0.30 mmol)
and magnesium bromide (9 mg, 0.03 mmol ) successively under nitrogen
with stirring at room temperature. The mixture was stirred for 12 h at the
same temperature. The mixture was filtered and concentrated in vacuo.
Purification by silica gel flash chromatography (EtOAc–n-hexane, 5 : 95)
provided 89% of 2a as a white solid. (R 5 Ph): Yield 89% (white solid); mp
92—94 uC; [a]2D4 5 +307.4 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) d
7.46–7.44 (d, J 5 7.5 Hz, 2H), 7.39–7.36 (m, 2H), 7.33–7.29 (m, 1H), 7.28–
7.24 (m, 2H), 7.18–7.16 (dd, J 5 8.5, 1.5 Hz, 2H), 7.00–6.96 (tt, J 5 7.0,
1.5 Hz, 1H), 5.52 (q, J 5 7.0 Hz, 1H), 4.81 (dt, J 5 9.0, 4.5 Hz, 1H) 4.77
(dd, J 5 9.0, 5.0 Hz, 1H), 3.47 (dd, J 5 9.0, 5.0 Hz, 1H) ), 3.35 (t, J 5
9.0 Hz, 1H), 2.04–2.00 (m, 1H), 1.91–1.85 (m, 1H), 1.74–1.72 (m, 1H),
1.71–1.69 (m, 1H), 1.58 (d, J 5 7.5 Hz, 3H), 1.59–1.45 (m, 2H), 1.12–1.01
Scheme 2 Stereochemical identification of the reaction product.
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Chem. Commun., 2005, 3062–3064 | 3063

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(m, 3H), 0.93 (dd, J 5 5.0, 2.0 Hz, 6H), 0.76 (d, J 5 7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 169.2, 150.9, 147.4, 139.5, 128.6, 128.4, 127.7, 127.3,
123.5, 122.2, 76.7, 76.3, 72.7, 51.3, 46.9, 44.3, 44.3, 40.6, 34.0, 31.4, 26.1,
23.1, 21.9, 20.8, 16.2, 16.0; IR (CH2Cl2) n(CLO) 1746 cm21, n(CLO)
1684 cm21; Anal. Calcd for C28H36N2O3: C, 74.95; H, 7.98; N, 6.41.
Found: C, 74.97; H, 8.09; N, 6.24%; HRMS (EI) m/z exact mass calcd for
C28H36N2O3: 448.2726, found 448.2719.
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